The goal of this project is to investigate the etiology and pathogenesis of congenital contractures. This will be accomplished by characterizing the extent to which genes that encode sarcomeric proteins of fast-twitch myofibers cause contractures in a group of syndromes collectively called the distal arthrogryposes (DAs). Each DA syndrome, of which there are ten (i.e., DA1-DA10), is typified by dominantly inherited non-progressive contractures of the, hand, hips, and feet (e.g., clubfoot)--the body areas most commonly affected by isolated contractures. The two most common forms of DA, DA1 and DA2B, are caused by mutations in TPM2 and TNNI2 or TNNT3, respectively, each of which encodes a component of the troponin-tropomyosin complex of fasttwitch myofibers. Thus, DA syndromes are new and a unique class of muscle disease caused by congenital perturbation of the fast-twitch contractile apparatus. Using a collection of 118 families and approximately 400 cases with DA, including several large, multiplex pedigrees, we propose to: (1) perform a genome-wide screen to identify additional positional candidate genes for congenital contractures; (2) screen DA cases for mutations in positional candidate genes and functional candidate genes that encode candidate sarcomeric proteins; (3) characterize the gross, histological, and ultrastructural characteristics of muscles of individuals with mutations in genes that encode sarcomeric proteins; and (4) investigate the relationship between disease-causing mutations, mRNA expression, protein expression, and phenotypic characteristics of individuals with DA. The data generated herein will provide us with an opportunity to (1) directly study the pathogenesis of congenital contractures, (2) design in-vitro studies of contractility with mutant proteins, (3) plan a strategy for developing an animal model of congenital contractures, (4) consider novel therapeutic interventions, and (5) test whether genes that cause DA syndromes are associated with susceptibility to idiopathic clubfoot.